Incidence of oropharyngeal candidiasis has risen dramatically due to increased antibiotic usage and longer survival of individuals with compromised immune systems including patients on cancer chemotherapy, diabetics, AIDS patients and premature infants. Relatively few antifungal drugs are available for clinical treatment of oral or systemic candidiasis. Increased use of these agents to treat candidiasis in late stage AIDS and cancer patients has resulted in emergence of Candidal species with antifungal drug resistance, especially to azole-based drugs. Histatins (Hsts) are small cationic polypeptides produced by human major salivary glands. In vitro, Hst 5 is the most potent candidacidal member of the family which kills 90% to 100% of Candida species at physiological concentrations. Hsts' potent antifungal activity, lack of toxicity to humans and ability to kill azole-resistant yeast strains underscore the importance of detailed understanding of their mechanism of action. Improvements in candidacidal function of Hsts and development of oral Hst delivery systems also require information about the Hst-induced cascade of cellular events leading to C. albicans death. Previous studies showed that Hst mechanism of action is unique from other characterized antimycotic drugs in that induction of lethal effect is through a novel pathway initiated by ATP efflux from C. albicans cells, which occurs while the cell membrane is intact. Studies are proposed to examine related properties of Hst-induced ATP release, its cellular effects following Hst-induced ATP release leading to cell death, requirements for intracellular transport of Hst for candidacidal activity and examine potential involvement of cAMP, ABC transporters and purinergic receptors in C. albicans response to Hst 5. These studies will contribute to characterization of novel intracellular pathways utilized by Hst to cause yeast cell death and lead to further understanding of the role of ATP efflux as a cell regulatory or signaling process.